Preparations of thiophosphites and thiophosphonates

Abstract

Improved methods for converting phosphite or phosphonate esters into corresponding thiophosphites or thiophosphonates and for synthesizing specific thiophosphite and thiophosphonate compounds so produced are disclosed and claimed. The methods start from phosphite diesters using P4S10 as the thionation reagent. The reaction mixture is refluxed until the reaction is complete and may be followed by separation and chloroformate ester phosphonation steps to produce pure thiophosphonocarboxylate triesters. Alternatively, these esters may be prepared directly by action of P4S10 on the corresponding phosphonocarboxylate esters. The former method was used to prepare dimethyl thiophosphite and thence trimethyl thiophosphonoformate, a key intermediate in synthesis of salts of thiophosphonoformic acid, which have anti-viral properties.

What is claimed is:  
     
       1. A method for the production of thiophosphonoformate esters having the formula                    
       the method comprising the steps of: 
       (a) forming a reaction mixture of a phosphonoformate ester having the formula                    
        an effective amount of tetraphosphorus decasulfide, and a suitable solvent, wherein R 1 , R 2 , and R 3 are each a substituted or unsubstituted alkyl, alkenyl, alkynyl, or aryl or a suitable protecting group; and  
       (b) heating said reaction mixture under a suitable temperature until conversion of the phosphonoformate ester (4) to the thiophosphonoformate ester (3) is substantially complete.  
     
     
       2. The method of claim  1 , wherein the alkyl, alkenyl or alkynyl is C 1-24  alkyl, alkenyl or alkynyl; the aryl is phenyl; and the suitable protecting group is trimethylsilyl, benzyl, or pivaloyloxymethyl. 
     
     
       3. The method of claim  1 , wherein the suitable solvent is a nonpolar or aprotic solvent. 
     
     
       4. The method of claim  3 , wherein the nonpolar solvent is an aromatic solvent. 
     
     
       5. The method of claim  4 , wherein the aromatic solvent is selected from the group consisting of benzene and toluene. 
     
     
       6. The method of claim  3 , wherein the polar aprotic solvent is tetrahydrofuran. 
     
     
       7. The method of claim  1 , wherein the effective amount of tetraphosphorus decasulfide is between about 0.4-1.0:1.0 (P 4 S 10 :phosphonoformate). 
     
     
       8. The method of claim  7 , wherein the effective amount of tetraphosphorus decasulfide is about 0.5:1.0 (P 4 S 10 :phosphonoformate). 
     
     
       9. The method of claim  1 , wherein the suitable temperature is between about 60° C. to about 95° C. 
     
     
       10. The method of claim  9 , wherein the suitable temperature is between about 70° C. to about 80° C. 
     
     
       11. A method for the production of thiophosphonoformate esters having the formula                    
       the method comprising the steps of: 
       (a) forming a reaction mixture of a phosphonoformate ester having the formula                    
        an effective amount of tetraphosphorus decasulfide, and a suitable solvent, wherein R 1 , R 2  and R 3  are the same or dissimilar and are selected from the group consisting of C 1-24  alkyl and phenyl, wherein the suitable solvent is a nonpolar or polar aprotic solvent, whereby the effective amount of tetraphosphorus decasulfide is about 0.5:1.0 (P 4 S 10 :phosphonoformate); and  
       (b) heating said reaction mixture under a suitable temperature between about 70° C. to about 80° C. until conversion of the phosphonoformate ester (4) to the thiophosphonoformate ester (3) is substantially complete.  
     
     
       12. The method of claim  1 , further comprising the steps of: 
       (c) separating the thiophosphonoformate ester (3) from said reaction mixture; and  
       (d) hydrolyzing the thiophosphonoformate ester (3) to form thiophosphonoformic acids and their additional salts.